Oxazolines



OXAZOLINES Werner Meiser and Gerhard Domagk, Wuppertal-Elberfeld, Germany, assignors to Farbenfabriken Bayer Aktiengesellschaft, Leverkusen, Germany, a corporation of Germany No Drawing. Application May 31, 1956, Serial No. 588,245

Claims priority, application Germany June 4, 1955 6 Claims. (Cl. 260-307) The present invention relates to oxazolines and more particularly to oxazolines derived from azidoacrylaminophenylpropanediols. The azidoacylaminophenylpropanediols of the general formula described in our co-pending application Serial No. 561,- 642 have a very broad therapeutical action. For some purposes, for example when given to children, these compounds have the disadvantage of tasting bitter.

It is therefore an object of the present invention to provide highly active, but substantially tasteless compounds of this class.

A further object is the provision of valuable intermediates for the preparation of azidoacylami'nophenylpropanediols. Further objects will appear hereinafter.

We have found that such tasteless, yet active, compounds may be obtained by preparing the oxazolines which are in theory obtainable from the above azidoacylaminopropanediols by splitting off water. Since the formation of the oxazolines proceeds by either the l-hydroxy group of the 3-hydroxy group reacting with the nitrogen grouping, the following two isomers are possible and | C HaNa Since each of these oxazolines contains two asymmetric carbon atoms, it may occur in structural as well as optical isomers. These structural-isomeric forms, designated as erythro and threo form, may also occur as racemates. of the optically active isomers. Thus, every oxazoline may occur in six different forms, the D-, L- and DL-form of the threoand erythro series. It is thus possible to produce all these isomers dependent on which structurally or optically isomeric starting material is used. There is a similarity with the chloramphenicol series where this nomenclature has been generally accepted. The letters D and L do not signify the actual direction of rotation, they simply express the property of belonging to a definite series. The most important compounds, however, are the DL- and D-threo compounds of the two oxazolines, but the erythro compounds are also of importance since States Patent they may be converted by rearrangement into the compounds of the threo series.

The preparation of the oxazolines may be carried out by conventional methods, for example, by the action of azidoalkylene-nitriles on these aminopropanediols, if desired, in an anhydrous solvent, or by the action of azidoacylimido others or -thioethers on 2-aminopropane-L3-diol salts or vice versa of azidoacylimido ether salts or thioether salts on these aminopropanediols, whereby ring closure takes place withalcohol and ammonium chloride being split off. The reaction may be carried out, for example, in water, organic solvents or weak bases. In most cases, the two isomeric oxazolines are formed which may be separated by fractional crystallization. However, this separation is generally not necessary when using oxazolines for pharmaceutical purposes. It is possible to modify the production process so that practically only one of the two isomeric oxazolines is formed. Functional derivatives of the aminopropanediols modified in one of the hydroxy groups such as compounds substituted in 1- or 3-position, such as for example, esters or halogen compounds, may also be used as starting material according to the present invention. These functional derivatives are used with special advantage if a definite oxazoline is desired tobe obtained, or when subsequently introducing the nitro group. The substituents in the one hydroxy group are then split off again by conventional methods.

The azidoacylimino others are obtained by acting with a hydrogen halide upon a mixture of an azidoalkylnitrile and an alcohol in the presence of an inert solvent at a low temperature in the absence of moisture.

The oxazolines may also be obtained by bringing about a ring closure in the 2-azidoacylamino-1.3-propanediols which may be nitrated in p-position of the phenyl radical and which have been described in our co-pending application Serial No. 561,642 by a water-splitting ofi agent such as thionyl chloride, p-toluene sulphochloride or concentrated sulphuric acid. Functional derivatives of the azidoacylaminopropanediols modified in one of the hydroxy groups such as compounds substituted in 1- or 3- position such as, for example, esters or halides, may be used as starting materials according to the invention. These functional derivatives are used with special advantage if a definite oxazoline is desired to be obtained or when subsequently nitrating.

Esters of azidoacylaminopropanediols, such as 1- or 3-hydrohalic acid esters or 1- or 3-nitrous acid esters, may also be made to eliminate acid by the action of alkali with the formation of oxazoline.

Oxazolines may also be obtained by subjecting oxazoline esters, which may be prepared by reacting p-nitrophenyl-serine esters with azidoacylimino ethers, to a selective reduction with, for example, alkali metal or alkali metal boron hydn'des.

The following examples are given for the purpose of illustrating the invention.

Example 1 ice for 3 hours, the solution is poured into 2.5 liters of ice water and the precipitate is filtered otf by suction. It represents one of the isomeric D-threo-oxazolines having the formula shown on page 2, in a practically pure state. (Melting point 92 C.) [a] =|-8.5 (acetic acid ester). It becomes completely pure by recrystallising from 3 dilute methanol, having amelting point of 94 [a] =+8.66 (acetic acid).

Example 2 2.5 grams propane-1.3-diol are dissolved in milliliters of 96 percent methanol and stirred with 2.4 grams of .azidoacetimidoethyl ether hydrochloride at room temperature for 20 hours. The methanol is then distilled off in vacuo, the residue is suspended in a little water and filtered off by suction. Recrystallised from dilute methanol, the same product is obtained as described in Example 1 having a melting point of 94 C. From the mother liquors and by recrystallisation from an inert solvent there is obtained by evaporation in vacuo the isomeric oxazoline.

Example 3 4.3 grams of D-(-)-threo-l-p-nitrophenyl-Z-aminopropane-1.3-diol are dissolved in milliliters of percent ethanol and stirred with 3.7 grams of azidoacetimidoethyl. ether hydrochloride for 20 hours. After working up according to Example 2, the oxazoline is obtained again having a melting point of 94 C.

Example 4 4.24 grams of DL-threo-1-p-nitropheny1-2-aminopropane-1.3diol are dissolved in 25.5 milliliters of pyridine and treated with, azidoacetimido-methyl ether hydrochloride (decomposition at 102 C.), prepared by reacting azidoa-cetonitrile with methanol and hydrogen chloride while cooling with ice. After stirring and cooling with ice for 3 hours, the mass is poured into milliliters of icewater. The product filtered off by suction is recrystallized from dilute methanol. White crystals of a BL- threo-oxazoline are obtained of melting point 112 C.

Example 5 5 grams of D-(-)-threo-l-p-nitrophenyl-Z-aminopropane-1.3-diol are suspended in 33 milliliters of water and rapidly stirred with 5 grams of azidoaoetimidoethyl ether hydrochloride. The mass dissolves and crystallizes again after a short time. After stirring for 1 hour, the product is filtered off by suction and washed with water. An isomeric mixture of the two D-threo-oxazolines is obtained with an approximate rotation of [a] =29 (acetic acid). By repeated recrystallization from dilute methanol, the dextro rotary oxazoline as described in Example 1 can be obtained. By recrystallization from benzene or acetic acid the levo rotary isomeric D-threooxazoline is obtained.

Example 6 4.25 grams of DL-threo-1-p-nitrophenyl-Z-amino-propane-1.3-diol are suspended in 24 milliliters of water and treated with 3.6 grams of acetimidoethyl ether hydrochloride. By vigorous stirring the mass enters into solution and crystallization of the oxazoline sets in soon. After stirring for 1 hour, the reaction product is filtered oli by suction and recrystallized from dilute methanol. An isomeric mixture of the two DL-threo-oxazolines is obtained having an approximate melting point of 99-- 104 C. and which may be separated, if desired.

Example 7 2 grams of F-(oc)-threo-1-p-nitrophenyl2-'azidoacetylamino-3-benzoyl-hydroxy-propanob( 1) of melting point 168 C. are introduced with thorough cooling into 2 milliliters of purified thionyl chloride. Dissolution starts after a short time. The solution is allowed to stand overnight in a refrigerator, and then poured into pure ether and the viscous colourless oil thus obtained is repeatedly decanted with ether. By recrystallization from carbon tetrachloride, D threo 2 azidomethyl 5 p nitrophenyl 4 benzoyl hydroxy methyl oxazoline hydrochloride is obtained in the form of a white powder.

4 Example 8 1.67 grams of DL-threo-l-phenyl-Z-aminopropane 1.3- diol is suspended in 6 milliliters of water and treated with 1.8 grams of azidoacetimidoethyl ether hydrochloride. The mass dissolves and an oil separates out after a short time. After stirring for 1 hour, the oil is taken up in methylene chloride and shaken out once with water. After drying over sodium sulphate and evaporating in vacuo, the isomeric mixture of the DL-threo-oxazolincs is obtained as an oil, free from nitro groups.

Example 9 2.12 grams of D-(-)-threo-l-p-nitrophenyl-Z-aminopropane-1.3-diol are dissolved in 12.5 milliliters of pyri dine and treated with ice cooling with 1.8 grams of a-azidopropioniminomethyl ether hydrochloride (decomposition at 79 (3., prepared by reacting azidopropionitrile with methanol and hydrogen chloride). After stirring for 3 hours and cooling with ice, the reaction product is poured into 60 milliliters of ice water and the precipitated oil is taken up in methylene chloride. After shaking out with water .and drying, the isomeric mixture of D threo 2 a azid'oethyl 5 p nitrophenyl 4 hydroxy-met-hyloxazoline and D-threo-2-a-azidoethyl-4-pnitrophenyl-hydroxy-methyl-oxazoline is obtained as an oil.

Example 10 8 grams of D-(-)-threo-1-p-nitrophenyl-2-azidoacetylamino-1.3-dichloropropane (decomposition at 131 C.) are dissolved in milliliters of alcohol and 25 milliliters of 1 N sodium hydroxide are added thereto drop- Wise at about 25 C. The solution is stirred for a further two hours and then neutralised with 1N sulphuric acid. It is evaporated in vacuum to dryness, the residue is suspended with a little water, filtered off by suction and recrystallised from dilute methanol. The white crystals of D threo 2 azidomethyl 5 p nitrophenyl 4- chlono-methyl-oxazoline are obtained which decomposes at 144 C. and may be converted into D-threo-2-azidomethyl-S-p-nitropheny1-4-hydroxy-methyloxazoline by alkaline hydrolysis.

Example 11 1.45 grams of DL-threo-2-azidomethyl-S-p-nitrophcnyloxazolinel-carboxylic acid ethyl ester (melting point 138 C.), obtained from p-nitro-phenyl-serine-cthyl ester and azidoacetimidoether hydrochloride in alcoholic solution are dissolved. in 9 milliliters of tetrahydrofurane, treated with milligrams of sodium boron hydride and then with 680 milligrams of calcium iodide at +2 C. Stirring is continued for a further 2 hours with ice cooling and for 3 hours at room temperature. The solution is then treated with 40 milliliters of ice water and ad justed to pH 7 with dilute hydrochloric acid. After stirring for some hours, the solution is completely extracted with acetic acid, dried over sodium sulphate and distilled off in vacuo. Recrystallized from dilute methanol, D1.- threo 2 azidomethyl 5 p nitrophenyl 4 hydroxymethyl-oxazoline is obtained having a melting point of 118 C.

We claim:

1. A member of the group consisting of oxazolines of the formulae z-Oon c JH-omoa C I C and 5 wherein R is a member of the group consisting of H '6. D threo 2 m -azidoethy1 p nitrophenyl hyand an acyl group, and x is a member of the group condroxy methyl-oxazoline. sisting :of hydrogen and the nitro-group.

2. DL threo 2 a id mefl1y1 5 P nitpophenyl 4- References Cited in the file of this patent yg sy m(et'h3;1- oxl211z0'line.2 d th 1 5 t 5 UNITED STATES PATENTS -treo- -'az1om'ey- -p-m'rol phenyl-4-hydroxy methy1-oxazo1ine. 2513346 Moersch et July 1950 4 D three 2 kazidomethyl 5 P i 2,727,070 Jacob 1955 2,759,001 M oersch et a1 Aug. 14, 1956 phenyl-4-hydroxy methyl-oxazoline.

5. DL threo 2 -'azidomethy1- 5 phenyl 4 hydroxy 10 methyloxazoline. 

1. A MEMBER OF THE GROUP CONSISTING OF OXAZOLINES OF THE FORMULAE 